Editor’s Note: This article is in response to Mueller M., Biener M., Vafaie M., Doerr S., Keller T., Blankenberg S., et al. Absolute and Relative Kinetic Changes of High-Sensitivity Cardiac Troponin T in Acute Coronary Syndrome and in Patients with Increased Troponin in the Absence of Acute Coronary Syndrome. Clinical Chemistry 2012; 58:209-218.

Article Summary

Detection of cardiac troponin (cTn) is common in non-acute coronary syndrome (ACS) patients and appears to be higher with high-sensitivity cTn (hs-cTn) assays. Current guidelines for diagnosing acute myocardial infarction (MI) require at least one cTn value >99th percentile for that assay, in conjunction with a serial rise in fall in cTn(1). In this context, the authors sought to determine whether relative or absolute change in hs-cTnT was better for differentiating ACS and non-ACS patients.

Hs-cTnT was serially measured in 784 consecutive patients without ST-elevation or LBBB presenting to the emergency department who underwent an evaluation for ACS. Patients with ACS who had at least 2 hs-cTnT measurements within 6 h and non-ACS patients with hs-cTnT concentrations above the 99th percentile value (14 ng/L) were studied to compare absolute and relative kinetic changes of hs-cTnT.

For discrimination of non-STEMI (n=165), the absolute change using the ROC-optimized value of 9.2 ng/L had a positive and negative predictive value of 49% and 96.5%, an area under the curve of 0.898 and was superior to all relative hs-cTnT changes (P<0.0001). In contrast, relative changes had an area under the curve of only 0.752. In the NSTEACS group (n=342), the absolute change using an ROC-optimized value of 6.9 ng/L had a positive and negative predictive value of 83% and 93%. When compared to the ≥20% relative change, the ROC-optimized absolute change added significantly to both the entire study population and for the ACS cohort (net reclassification index 0.331 and 0.499, P<0.0001).

The authors concluded that absolute changes appear superior to relative changes in hs-cTnT for discriminating between patients with and without non-STEMI.A rise or fall of at least 9.2 ng/L in the overall study population performed well for excluding non-STEMI. However, delta values were useful to rule-in non-STEMI only in a specific ACS population.

Commentary

How to determine which patients presenting to Emergency Departments who have an elevated cardiac troponin actually represents a true ACS is a common and important clinical issue. This challenging clinical problem has only been magnified by the newer high-sensitivity (hs) cardiac troponin (cTn) assays. A change over time of cTn values, or lack there of, is an important element in evaluating these patients. The universal definition of acute myocardial infarction (AMI) states that a “rise and/or fall” of cardiac markers is required to identify AMI.1 Although current recommendations are to use a percent change in value, much uncertainty still exists on exactly what constitutes a significant change. Mueller and colleagues should be commended on a unique study design that investigated the diagnostic accuracy of changes of a hs-cTnT assay over 3-6 hours.2 Prior studies have typically included patients with non-cardiac diagnoses and normal cardiac troponin values. In contrast, patients ultimately found to not have suffered an ACS were only included in this study if they had an elevated cTnT above the 99th percentile. Thus, the study was enriched with the most challenging population of patients, those without ACS but with an elevated hs-cTnT.

The authors evaluated a the hs-cTnT Roche assay (available for commercial use in Germany but not in the US) which has a 99th percentile value of 14 ng/L (equivalent to 14 pg/ml). They found that that an absolute change of 9.2 ng/L had the highest diagnostic accuracy and was superior to all percentage changes. This absolute change had a NPV for NSTEMI of 96.5%, but a PPV of only 49 %. Accordingly many patients without such a change could have NSTEMI excluded, but those with such a change would need further evaluation. These results are consistent with a prior study that found that absolute changes using the same hs-cTnT were superior to percentage changes, and the optimal cut-point was similar at 7 ng/L.³ These studies represent a significant step forward and offer guidance in regards to what change in hs-cTn over time should be considered significant. However, these results need to be viewed with some caution.

First, when considering small changes of cTn over relatively short periods of time, the exact timing of draws can be critical. Patients in the study had an hs-cTnT at presentation and at least one second draw “after 3 or 6 hours”. The exact timing of these draws is unclear. Second, the biological variation of individual assays will need to be carefully characterized to distinguish true dynamic pathologic changes from normal physiologic variation. One study investigating biological variation in a normal population with a hs-cTnT assay suggested that an 85% change over 6 hours would be significant.⁴ Third, since there is no standardization among cTnI assays, the most appropriate cut-points for changes over time will need to be determined for each particular assay. Fourth, the authors required that patients have at least a 20% increase of hs-cTnT for the diagnosis of NSTEMI, including all available values over 24 hours, and have at least an absolute concentration change of ≥5 ng/L between the baseline and highest value. Patients who did not meet these criteria but had a suggestive history for acute ischemia or other supportive testing were classified as unstable angina. Likely some of these patients should have been classified as NSTEMI.

Despite these limitations, this study does offer important guidance on what should be considered a significant change in hs-cTnT for diagnosing NSTEMI. Clearly further studies, hopefully multi-center, are required before firm recommendations can be made on specific criteria that should be used to indicate a significant change in hs-cTn values for guiding medical decision making.

References

1. Thygesen K., Alpert J.S., White H.D., Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007; 50:2173-2195.
2. Mueller M., Biener M., Vafaie M., Doerr S., Keller T., Blankenberg S., et al. Absolute and Relative Kinetic Changes of High-Sensitivity Cardiac Troponin T in Acute Coronary Syndrome and in Patients with Increased Troponin in the Absence of Acute Coronary Syndrome. Clin Chem 2012; 58:209-218.
3. Reichlin T., Irfan A., Twerenbold R., Reiter M., Hochholzer W., Burkhalter H., et al.Utility of absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation 2011; 124:136-145.
4. Vasile V.C., Saenger A.K., Kroning J.M., Jaffe A.S. Biological and analytical variability of a novel high-sensitivity cardiac troponin T assay. Clin Chem 2010; 56:1086-1090.

Keywords: Acute Coronary Syndrome, Arrhythmias, Cardiac, Heart Conduction System, Myocardial Infarction, Troponin T

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